1. Field of the Invention
This invention relates to devices for measuring the concentration of certain biochemical constituents in a patient. More particularly, the invention also relates to sensor units which may be placed under a patient's skin and which are used in conjunction with remote detection means to sense properties of a sample analyte.
2. Description of the Prior Art
It has become increasingly important in analytical and clinical chemistry to have the capability of remote sensing of chemical and physical parameters. Some methods of performing this type of sensing have been known, such as potentiometry, amperometry, piezoelectric mass determination, conductivity and measurement of reaction enthalpy.
In addition to these methods, optical fibers can be used for remote sensing of analytes and other substances. Optical sensors have certain advantages over electrochemical sensors. For example, optical sensors are immune to electromagnetic interferences. Further, the use of optical fibers can be advantageous when the samples are relatively inaccessible, for instance, in case of in vivo tests. Optical fiber wave guides allow the transportation of an optical signal over large distances from the sample to an associated meter, for example. Optical fibers can be exposed to varying environments without suffering substantial destruction or deterioration as a result. For a general discussion of sensors and of optical fiber sensors in particular see Wolfbeis, Fibre-optic Sensors in Biomedical Sciences, Pure and Appl. Chemistry, Vol. 59, No. 5 pp. 663-672 (1987). See also U.S. Pat. Nos. 4,954,318 and 4,999,306.
It has been known to provide optical fiber sensors of various types. The disclosure of U.S. Pat. No. 4,334,438, is hereby incorporated herein by reference. This patent relates to a fiber optic sensor having a chamber containing a dialysis membrane which allows selected plasma constituents to pass therethrough and enter the chamber. The chamber contains specific receptor sites in the form of binding agents each of which reversibly binds with one of the plasma constituents. The chamber also contains competing ligands which are dye-labeled. They compete with the plasma constituents for the specific receptor sites on the binding agents. The competing ligands are chosen for their particular optical properties and molecular size so that they do not escape back out of the sensor into the bloodstream. The intensity of light emitted from or absorbed by the receptor-site/competing ligand complexes or the free competing ligand alone can be measured by a fluorimeter. This measurement gives a quantitative indication of the concentration of plasma constituents in the blood.
One limitation of the system of U.S. Pat. No. 4,334,438 is that the response time is on the order of minutes due to the time it takes for diffusion of the molecules being studied across the membrane and along the chamber. Further, as the fluorescently labeled compound is bound to the wail, the optical fiber must be inserted exactly straight inside the hollow fiber so that the amount of baseline fluorescence due to the dye-labeled competing ligand bound to the wall is minimized. Further, the skin of the membrane must remain immersed in a buffer solution during storage of the sensor. Otherwise, if it is exposed to air, the membrane begins to dry and subsequent diffusion of the analyte into the sensor is dramatically affected. Because of this, the assembly must be glued together while it is submerged in the buffer. The glue seams must form a tight seal because with any leak, the chemical constituents of the sensor can escape. The optical fiber within the hollow fiber configuration can also exhibit lack of stability such that any relative movement between the two fibers while in use affects the signal response. In addition, during assembly the proteins which are immobilized are pumped through the fiber under the influence of pressure. This flow method results in variations in the amount of immobilized material along the inside wall, due to variations in the spongy surface causing a variability in the calibration curves between sensors during manufacture. There remains a need, therefore, for a sensor which overcomes these disadvantages.
Systems such as the one described hereinabove also present another problem. If the device is to be used on a patient, a chronic invasive connection through the skin must be maintained. This can result in a host of problems and annoyances when taking measurements. There remains a need, therefore, for a device that may be used in vivo without the need for chronic connections through the skin.
It has also been known to provide other types of fiber optic sensors. For example, U.S. Pat. No. 4,892,383 discloses a fiber optic sensor which includes a modular reservoir cell body and a semi-permeable membrane, however, the sensor requires use of a reagent which precludes reversibility. See also U.S. Pat. No. 4,892,640 which discloses a sensor for determining electrolytic concentrations using an ion selective membrane.
U.S. Pat. No. 4,849,172 discloses an optical sensor having a gas permeable silicone matrix that contains a high concentration of an optical indicator consisting essentially of a mixture of derivatives of a polynuclear aromatic compound. U.S. Pat. No. 4,857,273 discloses another type of sensor involving enhancement of a light signal response by incorporating a partially reflecting, partially transmitting medium between a coupling structure and an optically dense body.
Optical sensors based on generating a resonance signal in a metallic medium have also been known. See U.S. Pat. No. 4,877,747. Other sensors based on detection of refractive index charges in gaseous liquids, solids or porous samples have been known. See U.S. Pat. No. 4,815,843 and U.S. Pat. No. 4,755,667. Sensors for measuring salt concentrations have also been known. U.S. Pat. No. 4,572,106.
U.S. Pat. No. 4,577,106 discloses a remote multi-position information gathering system for obtaining thermometric information from remote locations using fiber optics.
U.S. Pat. No. 4,861,727 discloses a luminescent oxygen sensor using a lanthanide complex. U.S. Pat. No. 4,558,014 discloses assay apparatus employing fluorescence.
Other methods of measuring concentrations of biochemicals in blood include withdrawing blood from the patient for analysis. For example, U.S. Pat. No. 3,785,772 discloses a device having a pair of syringes to withdraw blood from a patient, and a dialysis membrane to separate a particular blood constituent from the blood, a reactant which reacts with the chosen blood constituent to form a reactant-blood constituent complex the concentration of which is proportional to the concentration of the blood constituent. This system requires replacement of the reactant after each measurement because the reactant and the blood constituent form an irreversible complex. In addition, the system cannot measure an instantaneous change in the concentration of the blood constituent because of the time taken to remove the blood from the body and obtain a reaction with the reactant.
U.S. Pat. No. 3,638,639 also discloses measurement of blood constituents outside the body. In this system, a catheter is inserted into the blood and lipids are passed through a membrane in the catheter and are dissolved in a solvent which is removed from the body to be analyzed.
U.S. Pat. No. 3,939,350 shows a system for carrying out immunoassays using fluorescence to indicate the presence of a ligand to be detected. An analog liquid is bound to a transparent sheet and contacted with an aqueous assay solution containing the ligand to be detected associated with fluorescent molecules. The ligands become bonded to the sheet and light is passed therethrough to cause fluorescence.
U.S. Pat. Nos. 3,123,866, 3,461,856 and 3,787,119, all disclose means to measure properties of the blood in vivo. These systems comprise optical catheters inserted into the blood for measuring the intensity of light reflected from the blood thereby indicating the blood's oxygen content. None of the aforementioned patents, however, are specifically designed for measuring the concentration of plasma constituents, such as glucose, in a continuous, reversible manner.
It has also been known to employ oximeters, which are photoelectric photometers, to noninvasively estimate the extent of blood oxygenation. These systems are noninvasive and employ no reagents.
U.S. Pat. No. 5,143,066 owned by the assignee of the present invention is expressly incorporated by reference herein. It discloses a system for measuring properties of certain substances designated as analytes. A probe housing has an optical fiber associated therewith and has a membrane which is permeable to the analyte being studied. The housing has a reflective surface member disposed between the optical fiber and membrane to define a dark chamber which does not allow light from the optical fiber to enter or exit the chamber. A dye-labelled analog-analyte can pass through the reflective member to permit it to enter an adjacent light chamber where measurements related to the concentration of the analyte may be made. Excitation light from an optical fiber is received within the light chamber. Immobilized receptors are provided within the housing preferably in the dark chamber. The dye-labelled analog-analyte and analyte compete to bind with the immobilized receptors. The dye-containing analog-analyte molecules which do not bind to immobilized receptors pass through the reflective surface member to the light chamber. A light source acting through the optical fiber creates responsive fluorescent light to be emitted by the dye-containing analog-analyte with such responsive light being carried to the detector means. The detector means employ this fluorescent light to determine concentration of the analyte in the sample. In one embodiment, an in vivo sensor which may be placed under the skin is employed. This system, however, employs two chambers alone with fiber optic means and a reflective divider between the two chambers.
Despite these prior art methods and devices, there remains a need for a sensor which has increased sensitivity and a shorter response time. Further, there remains a need for a device where the active element is of shorter length and a sensor which is easier to assemble than conventional designs. There remains a further need for a device and method which may be used to measure either free dye-containing molecules or bound dye-containing molecules and which has the capability of providing continuous monitoring of the concentration of an analyte.
There is also a need for a sensor device used for the continuous monitoring of biochemicals which may be used in vivo without the need for chronic connections through the patient's skin. Therefore, there remains a need for a less-invasive device for in vivo sensing of analyte properties which does not require the use of chronic connections through the skin.